Circadian Time-Dependent Kinetics of Theophylline and Its Modulation by Phenobarbital Pretreatment in Rats

The pharmacokinetics of theophylline (TPH, 10 mg/kg i.v.) were assessed in rats (natural light-dark span, June 9–10) after i.p. pretreatment with saline and 80 mg/kg phenobarbital (PB), respectively, for 3 consecutive days at either 07:00 h or at 19:000 h. Serum concentrations of TPH were assayed by high-performance liquid chromatography. No significant differences of the elimination rates of TPH could be found between the times of TPH administration (clearance: 1.17 ± 0.17 ml/kg/min at 07:00 h vs. 1.23 ± 0.17 ml/kg/min at 19:00 hours). PB premedication markedly accelerated TPH elimination. The increase in clearance values was more expressed when TPH was injected at 07:00 h than at 19:00 h (2.48 ± 0.67 vs. 2.06 ± 0.41 ml/kg/min, p < 0.01).     

Circadian Variation in the Gastric-Emptying Response to Eating in Rats Previously Fed Once or Twice Daily

Four experiments dealt with circadian variation in the gastric emptying (GE) response to eating, among rats accustomed to eating once (1X) or twice daily (2x). In measuring GE response, a test meal [10 g accustomed diet per (kg body weight)^3/4] was fed close to a scheduled eating time or after a delay of up to 24 h. GE response was the fraction of the ingested test meal emptied per hr, up to a known degree of emptying, e.g., 50-58% of the test meal. Animals accustomed to the prescribed eating patterns ate promptly and at similarly rapid rates at all times of day. GE response, as plotted against time of response, fit a 24-h cosine model. Acrophase (time of maximum GE response of the fitted model) was similar, being 1.5 and 2.1 h, respectively, after the starting time of the accustomed dark-span meal for 1X and 2x rats, while amplitude (1/2 the maximum-to-minimum difference) was 41 and 24% of the MESOR (rhythm-adjusted mean). Characteristics of the GE rhythm appeared to be unchanged among 1X rats, severely versus minimally restricted in food intake during a final 9 days.     

Cerebral Cortical Glucose Utilization in the Conscious Rat: Evidence for a Circadian Rhythm

Abstract: The presence of a circadian rhythm of glucose utilization was demonstrated in vivo in rat cerebral cortex. The activity pattern of the rats, living in a controlled lighting regimen with lights on from 7 a.m. to 7 p. m., appeared to coincide with the rate of glucose consumption in the brain. The rate of utilization was measured at 3-h intervals throughout the day and was found to fall from a maximum at 3 a.m. of 0.98 ± 0.13 μmol min⁻¹ g⁻¹ to a minimum of 0.70 ± 0.08 μmol min⁻¹ g⁻¹ at 3 p. m. Brain glucose also varied with time and its fluctuating level weakly correlated with its rate of utilization. Animals entrained on a 5-h (4: 30-9: 30 p. m.) feeding schedule had a similar circadian rhythm, with only a slight increase in amplitude. Reversal of the light cycle caused a disruption in the normal rhythm, but utilization still varied significantly with time of day. The results both indicate the potential error that can be encountered in experiments done at different times of the day and stress the need for awareness of time of day as a factor in measurements of alterations of metabolic rate in the brain.     

Circadian Variation in the Occurrence of Paroxysmal Supraventricular Tachycardia in Clinically Healthy Subjects

The purpose of this study was to assess prospectively the circadian distribution of spontaneous paroxysmal Supraventricular tachycardia (PSVT) in drug-free subjects with no previous history or symptoms and signs of concomitant heart or lung disease. Of 112,424 presumably diurnally active patients admitted to the Emergency Department of a city hospital during a 2-year period (1990-1991), a total of 185 patients were screened with these characteristics. Time of symptom onset was exactly recordable in 177 (75 men and 102 women). Analysis of variance documented a higher incidence in the morning-afternoon hours. Cosinor analysis, although not a perfect method for the time series analysis, verified circadian rhythmicity with afternoon peak times. Our findings suggest that a circadian pattern in intrinsic electrical instability of the heart conduction system exists irrespective of the circadian fluctuations in the pathophysiologic mechanisms of the cardiovascular or lung diseases most frequently associated with PSVT itself.     

Circadian Phase Variation in Bipolar I Disorder

Abnormalities in circadian rhythms are prominent features of bipolar I disorder (BD1). To investigate circadian variation in BD1, we evaluated morningness–eveningness (M/E), a stable trait reflecting circadian phase, using the composite scale (CS) among BD1 patients (DSM IV criteria; n=75), unscreened controls (n=349), and patients with schizophrenia (SZ) or schizoaffective disorder (SZA) (n=81). Our analyses showed that CS scores correlated significantly with age but did not differ by gender among the controls. BD1 patients differed significantly from controls and from SZ/SZA patients when age was considered. CS scores were distributed bi‐modally among BD1 cases. There are several possible reasons for the observed heterogeneity. Younger BD1 patients, and those with rapid mood swings, were significantly more likely to have lower CS scores (i.e., to score in the ‘evening’ range and to have later circadian phase). CS scores were also positively correlated with the age at onset and the duration of the most severe depressive episodes. These relationships were not observed among the SZ/SZA groups. Thus, distinct patterns of M/E were noted among BD1 patients and among BD1 subgroups. The impact of medication, mood state, and chronicity on CS scores needs to be considered.     

Gastric Potential Difference in Fasted Rats: Circadian Studies

The pathophysiology of gastroduodenal ulcer disease remains the subject of intense research and controversy. One model of gastric ulcerogenesis implicates a disruption of complementary circadian rhythms between protective and destructive factors. Parallel circadian rhythms have been reported between acid secretion and gastric potential difference (PD) in in vitro models. The purpose of this study was to investigate the circadian measurements of PD, a parameter of intact gastric mucosal function and thus a putative parameter of gastric protection, in intact, fasted, anesthetized rats. Sixty-four male Sprague-Dawley rats were acclimatized in sound-attenuating, lightproof chambers for 3 weeks on a 12:12-h light-dark schedule. Eight rats were fasted 18 h before being sampled at each of eight times on the circadian clock (01:00, 04:00, 07:00, 10:00, 13:00, 16:00, 19:00. and 22:00 hours after lights on) (HALO). In each rat, after anesthesia (ketamine/ acepromazine) and laparotomy, the tip of a catheter (pre-filled with KC1 agar) was passed into the gastric corpus through the duodenum. The tip of a second KC1-agar catheter was placed within the peritoneal cavity. The position of the intragas-tric catheter was gently adjusted for obtaining the highest stable PD reading. The data showed significantly higher values at 07:00 and 10:00 HALO. The lowest value was at 13:00 HALO. The difference between high (10:00 HALO) and low (13:00 HALO) values was 4.5 mV or 13% of the mean. This difference was highly significant (p = 0.003) Analysis of variance showed that the values at 07:00 and 10:00 HALO were significantly higher than the values at 01:00, 13:00, and 16:00 HALO. Thus, the existence of a circadian rhythm in gastric PD is supported.     

Circadian Variation of Fibrinolytic Activity in Blood

Approximately 35 years ago, it was discovered that spontaneous fibrinolytic activity in blood showed a sinusoidal variation with a period of 24 h; it increased severalfold during the day, reaching a peak at 6:OO p.m. and then dropped to trough levels at 3:00–4:00 a.m. The range of the fluctuation and the 24-h mean levels were highly reproducible within an individual; moreover, the timing of the oscillation was remarkably consistent among individuals, with a fixed phase relationship to external clock time. The biorhythm could not be accounted for simply by variations in physical activity, body posture, or sleepfwake schedule. Gender, ethnic origin, meals, or resting levels of blood fibrinolytic activity also did not influence the basic features of the rhythm. Older subjects, compared to younger ones, showed a blunted diurnal increase in fibrinolytic activity in blood. Recent studies have established that, of the known components of the fibrinolytic system, only tissue-type plasminogen activator (tPA) and its fast-acting inhibitor, plasminogen activator inhibitor- 1 (PAL l), show a marked circadian variation in plasma. In contrast, levels of plasminogen, α₂-antiplasmin, urinarytype plasminogen activator, and a reversible tPA inhibitor vary little or none during the 24 h. Quenching antibodies to tPA have shown that the circadian rhythm of fibrinolytic activity in blood is due exclusively to changes in tPA activity. However, the 24-h fluctuation of plasma tPA activity is phase shifted in relation to the rhythm of immunoreactive tPA, but shows a precise phase inversion with respect to the 24-h variation of PAL 1 activity and antigen. Therefore, plasma tPA activity, as currently measured in vitro, is tightly and inversely related to the levels of PAL 1 throughout the 24-h cycle. The factors controlling the rhythmicity of plasma PAI-1 are not fully elucidated but probably involve a humoral mechanism; changes in endothelial function, circulating platelet release. products, corticosteroids, catecholamines, insulin, activated protein C, or hepatic clearance do not appear to be responsible. Shift workers on weekly shift rotations show a disrupted 24-h rhythm of plasma tPA and PAL 1. In acute and chronic diseases, the circadian rhythmicity of fibrinolytic activity may show a variety of alterations, affecting the 24-h mean, the amplitude, or the timing of the fluctuation. It is advisable, therefore, to define the 24-h pattern of plasma tPA and PAI- 1 in patient groups, before levels based on a single blood sampling time are compared to those of a control population. In normal conditions, the 24-h variation of plasma tPA and PAI- 1 is not associated with parallel circadian changes in effective fibrinolysis, assessed as plasma D-dimer concentrations, presumably because fibrin generation in the circulation is low. In diseases in which fibrin formation is increased, however, the physiological drop of fibrinolytic activity in the morning hours may favour thrombus development at this time of day, in agreement with the reported higher morning frequency of acute thrombotic events.     

Circadian Variation in Allergen and Nonspecific Bronchial Responsiveness in Asthma

In a majority of patients, exacerbations of asthma occur more frequently during the night than day. Many hypotheses have been proposed to explain such variation in asthma. The airways of asthmatic persons are characterized by an abnormal degree of inflammation and bronchial hyperre-sponsiveness to both nonspecific and specific challenges. Studies of both children and adults with asthma document marked circadian rhythmicity in the response of airways to bronchial challenges with histamine, methacho-line, acetylcholine, saline, and house dust mite. Taken together, the findings of these investigations indicate that the hyperreactivity of airways to these agents is more profound and prolonged following evening and overnight tests compared to tests conducted in the midday and afternoon. The temporal pattern in bronchial response to the hyperventilation of cold dry air is different. The hyperresponsiveness of airways to this challenge is greatest in the afternoon. The amplitude of the circadian rhythm in airway hyperreactivity seems to be correlated to the amplitude of the circadian rhythm of pulmonary function; the greater the day-night difference in bronchial reactivity is, the greater is the day-night difference in flow rates.     

Circadian Variation in Human Performance Evaluated By the Walter Reed Performance

–As part of a two clock-time (0830 versus 2030) evaluation of administration-time dependent effects of dexedrine (S mg) and triazolam (0.25 mg) on human cognitive performance, placebo (control) studies were conducted on 12 diurnally active (0700–2300) male adults (23–38 yrs) using a double-blind, randomized crossover design. Testing was conducted hourly during a series of sleepless 13-hr spans commencing in the morning or evening, using the Walter Reed computer controlled and scored multi-task cognitive performance assessment battery. For the placebo condition, Single and Group Cosinor analyses documented circadian rhythms in performance for most tasks (reaction time, logical reasoning, serial add/subtract and spatial orientation) both for individuals and the group. Overall, performance was worse overnight, when sleepiness was greatest, and best between 1830 and 2030. It was most variable around 0600–0700. The day-night variation in performance over all cognitive tests amounted to 21% of the 24-hr mean.     

Circadian Variation of Cyclic AMP in the Rat Pineal Gland

Abstract: This study was carried out to investigate circadian variation of cyclic AMP contents in the rat pineal glands, using the high-energy microwave radiation technique. The pattern of cyclic AMP concentration in the pineal gland showed a distinct circadian variation, with the maximum level at 0200 and the lowest at 1400. The administration of propranolol completely blocked the dark-induced increase in the pineal cyclic AMP level at 0200, and the administration of isoproterenol induced a threefold, rapid increase in the cyclic AMP level at 1400, although it did not change the level at 0200.     

Feeding-Related Circadian Variation in tele-Methylhistamine Levels of Mouse and Rat Brains

Circadian changes in the brain histamine (HA) and tele-methylhistamine (t-MH) levels were studied in mice and rats after adaptation to an alternating 12-h light/dark cycle (lights on at 0600). Although there was no significant circadian fluctuation of the brain HA levels, the levels of t-MH, a major metabolite of brain HA, showed a marked circadian variation. In mice, the t-MH levels were about 80 ng/g from 1200 to 1800 but about two times higher values were obtained from 2400 to 0600 of the next morning. In rats, the t-MH levels ranged from 24 to 28 ng/g at 0600 and 1200, slightly increased at 1800, and reached at 2400 a peak twice as high as the levels seen during the light period. The t-MH levels again rapidly decreased during the subsequent 3 h. In mice fasted from 1200, the t-MH levels did not increase during the period of darkness. When mice were fed at 1200 after a 24-h fast, a significant increase in the t-MH levels was observed at 1800. There was no significant circadian variation of the HA and t-MH levels in the plasma of mice and rats. These results suggest that circadian variation in brain t-MH levels is related to feeding and possible subsequent changes in elimination of t-MH from the brain and/or turnover of HA in the brain. This phenomenon should be given due attention when HA dynamics in the brain are being assessed.     

Chronopharmacological Study of Cephalexin in Dogs

Recent studies have identified a 24 h rhythm in the expression and function of PEPT1 in rats, with significantly higher levels during the nighttime than daytime. Similarly, temporal variations have been described in glomerular filtration rate and renal blood flow, both being maximal during the activity phase and minimal during the rest phase in laboratory rodents. The aim of this study was to assess the hypothesis that the absorption of the first‐generation cephalosporin antibiotic cephalexin by dogs would be less and the elimination would be slower after evening (rest span) compared to morning (activity span) administration, and whether such administration‐time changes could impair the medication's predicted clinical efficacy. Six (3 male, 3 female; age 4.83±3.12 years) healthy beagle dogs were studied. Each dog received a single dose of 25 mg/kg of cephalexin monohydrate per os at 10∶00 and 22∶00 h, with a two‐week interval of time between the two clock‐time experiments. Plasma cephalexin concentrations were determined by microbiological assay. Cephalexin peak plasma concentration was significantly reduced to almost 77% of its value after the evening compared to morning (14.52±2.7 vs. 18.77±2.8 µg/mL) administration. The elimination half‐life was prolonged 1.5‐fold after the 22∶00 h compared to the 10∶00 h administration (2.69±0.9 vs. 1.79±0.2 h). The area under the curve and time to reach peak plasma concentration did not show significant administration‐time differences. The duration of time that cephalexin concentrations remained above the minimal inhibitory concentrations (MIC) for staphylococci susceptiblity (MIC=0.5 µg/mL) was>70% of each of the 12 h dosing intervals (i.e., 10∶00 and 22∶00 h). It can be concluded that cephalexin pharmacokinetics vary with time of day administration. The findings of this acute single‐dose study require confirmation by future steady‐state, multiple‐dose studies. If such studies are confirmatory, no administration‐time dose adjustment is required to ensure drug efficacy in dogs receiving an oral suspension of cephalexin in a dosage of 25 mg/kg at 12 h intervals.     

Aspirin, Platelet Aggregation, and the Circadian Variation of Acute Thrombotic Events

The onset of several acute cardiovascular diseases occurs in a circadian pattern, with a peak incidence in the hours soon after awakening. This finding, coupled with laboratory data that confirm a surge in platelet activation during the early morning hours, suggests that acute changes in platelet aggregability may be an important trigger of thrombosis. Therefore, the efficacy of antiplatelet agents, such as aspirin, in reducing risks of vascular occlusion may result, at least in part, from a blunting of these short-term changes in platelet aggregability. In this review, clinical and laboratory evidence describing these cyclical changes is discussed, as is current evidence of the effects of aspirin on platelet function and the circadian variation of acute thrombosis.     

Circadian Variation in Phototactic Behaviour of Walking Indian Catfish, Clarias batrachus

Temporal organization in phototactic rhythm in male Clarias batrachus was studied in a choice chamber consisting of a photic zone and an aphotic zone. Results indicate that most of the fishes exhibited a statistically significant 24-h variation in the frequency of visits to the photic zone with a peak frequency at late night or early morning. Cosinor analysis of phototactic index (PI) values also yielded comparable results. This behaviour of C. batrachus shows similarity with its other activities, like air gulping, surfacing, foraging or predation that occur chiefly at night. The light intensity at the surface of a natural water body is more than at the bottom, even at night. Therefore, the peak phototactic activity observed in C. batrachus in the night or early morning could be attributed to its daily migration from the bottom to the surface of the water bodies. The results of the present study might be useful in aquaculture practice and inland fishing.     

Aspirin,Platelet Aggregation,and the Circadian Variation of Acute Thrombotic Events

The onset of several acute cardiovascular diseases occurs in a circadian pattern, with a peak incidence in the hours soon after awakening. This finding, coupled with laboratory data that confirm a surge in platelet activation during the early morning hours, suggests that acute changes in platelet aggregability may be an important trigger of thrombosis. Therefore, the efficacy of antiplatelet agents, such as aspirin, in reducing risks of vascular occlusion may result, at least in part, from a blunting of these short-term changes in platelet aggregability. In this review, clinical and laboratory evidence describing these cyclical changes is discussed, as is current evidence of the effects of aspirin on platelet function and the circadian variation of acute thrombosis.     

Circadian Variation in Cortisol Reactivity to an Acute Stressor

To investigate the role of the circadian pacemaker in cortisol reactivity to a cold pressor challenge, 26 diurnally subjects participated in a constant‐routine protocol and were divided into two groups. Group 1 started immediately after a monitored sleep period at 09:00 h, while group 2 started 12 h later. After 2 h of adaptation, a cold pressor test was presented every 3 h. The cortisol response was assessed by means of saliva samples that were taken before and after the test. The pretest samples were considered to be base‐rate measures and base‐rate values as subtracted from post‐test values were considered as reactivity measures. Both measures showed distinct Time‐of‐Day variations (respectively: F_7,168 = 16.92, p < 0.001, ε = 0.383; and F_7,175 = 8.01, p < 0.001, ε = 0.523). These findings are interpreted as evidence for the existence of an endogenous circadian periodicity underlying the sensitivity of the hypothalamus–pituitary–adrenal (HPA)‐axis to acute stress.     

Circadian Variation in the Onset of Acute Cerebral Ischemia: Ethiopathogenetic Correlates in 80 Patients Given Angiography

In a continuous series of 80 acute ischemic hemispheric strokes, the onset of symptoms was between 6:01 a.m. and noon in 45% of cases, between noon and 6:00 p.m. in 22.5%, between 6:Ol p.m. and midnight in 31.25%, and between midnight and 6:00 a.m. in 1.25% (p < 0.0001). By means ofangiography and computerized tomography, and by detection of arterial and cardiac sources of emboli, four stroke subtypes were identified. Embolic and thrombotic strokes had their most frequent onset between 6:01 a.m. and noon (45% and 71%, respectively), whereas strokes of unknown origin and lacunar strokes were randomly distributed between 6:01 p.m. and midnight. The morning activation of the catecholaminergic system can account for this pattern of circadian onset of ischemic stroke.     

Circadian Variation of Myocardial Ischemia in Patients with Stable Coronary Artery Disease

The circadian variation of myocardial ischemia detected during 24-h ambulatory electrocardiographic monitoring (AEM) was analyzed in 123 patients with stable angina pectoris, positive exercise test, and angiographically proven coronary artery disease. A total of 437 ischemic episodes (ST-segment depression ≥ 1 mm and duration ≥ 1 min) were observed; 333 (76%) episodes remained asymptomatic, and only 104 (24%) episodes were accompanied by anginal pain. Ischemic episodes predominantly occurred during the morning hours, between 6 a.m. and noon, and another smaller peak was observed in the afternoon, between 4 and 5 p.m.; this diurnal pattern was influenced neither by the extent of coronary artery disease nor the degree of left ventricular dysfunction. The circadian variation was restricted to the 345 (78%) ischemic episodes preceded by increases in heart rate; the 92 (22%) episodes without prior heart rate changes occurred randomly throughout the day. The morning peak in ischemic episodes was not associated with less myocardial oxygen supply; in contrast, heart rate profile showed parallel increases during the morning and afternoon hours, indicating elevated myocardial demand during these periods. Ischemia-related ventricular arrhythmias were concentrated during the morning hours, but their overall prevalence was low-28 (6%) of 437 ischemic episodes. These findings may provide further insight into the pathomechanisms of acute clinical events in patients with coronary artery disease, since the circadian variation of myocardial ischemia is very similar to that observed for the onset of myocardial infarction and sudden cardiac death.     

Circadian Wheel-Running Activity of Rats Under Schedules of Limited Daily Access to Salt

Schedules of limited daily access to food result in 'anticipatory' activity preceding each daily feeding. It is well-established that such food-anticipatory activity depends on a food-entrainable circadian timing mechanism. In the present study, we sought to extend the generality of these results by maintaining rats in running wheels under schedules which provided access to salt solutions or to salty food for 2 hr each day. The animals were subjected to dietary, pharmacological and surgical treatments that promote salt appetite. However, we found no evidence for daily salt-anticipatory wheel running activity in any condition.     

Circadian Wheel-Running Activity of Rats Under Schedules of Limited Daily Access to Salt

Schedules of limited daily access to food result in 'anticipatory' activity preceding each daily feeding. It is well-established that such food-anticipatory activity depends on a food-entrainable circadian timing mechanism. In the present study, we sought to extend the generality of these results by maintaining rats in running wheels under schedules which provided access to salt solutions or to salty food for 2 hr each day. The animals were subjected to dietary, pharmacological and surgical treatments that promote salt appetite. However, we found no evidence for daily salt-anticipatory wheel running activity in any condition.